PROJECT SUMMARY/ABSTRACT Approximately 6.7 million American women are unable to become pregnant or carry a baby to term. Any environmental exposure that causes damage to the ovary has the potential to cause infertility in women. Phthalates represent a significant concern for human fertility because they have been associated with early menopause, decreased hormone levels, and early pregnancy loss in women. Studies in animal models suggest that phthalates may impair fertility through their ability to disrupt ovarian function. Ovarian follicles, the functional units of the ovary, exist in various stages of development that range from the most immature primordial follicles to the large pre-ovulatory follicles, the stage at which they capable of sustaining hormone production and ovulating of health oocyte. Survival and successful transition to the large pre-ovulatory follicle stage depends on the positive actions of various factors including follicle-stimulating hormone (FSH), insulin- like growth factor 1 (IGF1), and 17?-estradiol (E2) which form a pro-survival network critical for the maintenance of fertility. There is, therefore, a critical need to identify the interactions between phthalates and these pathways to improve our ability to characterize the risk posed by phthalates and identify biomarkers and pharmaceutical targets to screen and treat infertility due to endocrine disruption. The main objective of this proposal, is to use environmentally relevant exposures to phthalates to test the central hypothesis that phthalates target the FSH-IGF1-E2 system, compromise follicle-dependent processes, and cause premature ovarian failure by increasing the rate of ovarian follicle loss in mice. To achieve our goal, we propose to use three model phthalates (DBP, DEHP, BBP) to (1) determine whether environmentally relevant exposures to phthalates alter follicular dynamics and disrupt FSH-IGF1-E2 signaling, (2) determine whether environmentally relevant exposures to phthalates cause follicular death by increasing apoptosis, and (3) identify the phenotypes resulting from environmentally relevant exposures to phthalates on processes that rely on healthy ovarian follicles. These studies will use environmentally relevant exposures to identify which signaling pathways, follicle types and individual ovarian cell compartments are most sensitive to phthalates and establish the phenotypes that result from these relevant exposures. By doing so, this work will facilitate the characterization of the risks of phthalate exposure and provide leads for potential biomarkers and therapeutic targets to detect and treat phthalate-induced reproductive toxicity. Our team is well-positioned to successfully complete the proposed work based on experience and institutional resources as detailed in the application.